Germ cells are the founder cells of the gametes and, as such, they carry forward the genetic information of each individual, including all its defects, into future generations. Male and female infertility can result from disturbances during germ cell development, determination, migration, proliferation and survival. Our long-term goals are, to determine the molecular basis of normal development and physiology of germ cells and to understand the pathophysiologic consequences of mutations. We will do this by studying mutations that cause sterility. The focus of this particular proposal is to characterize the mouse mutation atrichosis (at) that causes male and female sterility and atrichous skin. The aims of this proposal are: 1) To identify the molecular basis of the (at) mutation. We have localized the (at) locus in a 270-kb region on mouse Chromosome 10. We have started candidate gene selection and mutation identification. We also propose to test the hypothesis that both the fur and the germ cell phenotypes are caused by the same mutation. 2) Identify the biochemical basis of the (at) mutation. Germ cell numbers in (at) mutants start as early as decline12.5 days postcoitum (d.p.c.) and are greatly reduced at 14.5 d.p.c. BrdU labeling showed that there were fewer proliferating germ cells at 12.5 d.p.c, in the (at) mutant. This leads to us to hypothesize that the (at) gene is required for germ cells to proliferate. We plan to carry out detailed experiments to determine a) if germ cell loss in (at)-/- mutants is due to inability to proliferate and when does the phenotype manifest and b) what signal pathways are involved with the (at) gene. 3) To determine cell autonomy of the (at) gene. This aim is designed to test the hypothesis that the (at) gene acts in a germ cell autonomous fashion and is based on previous studies that indicated the Sertoli cells were normal in (at)-/- mutants. We plan to conditionally target the (at) gene in embryonic germ cells using the Cre-loxP system to determine whether the (at) gene functions in the germ cells or in the surrounding somatic cells.